Local anesthetics must penetrate the epineurium, perineurium, and endoneurium in order to reach their intended sight of action. Consequently, local anesthetics require much higher concentrations to be effective when used clinically than in isolated nerves (Schwartz, et al., J Physiol, 233:167-194 (1973); Hahin, et al., J Gen Physiol, 78:113-139 (1981); Chernof, et al., Biophys J., 58:69-81 (1990); Lee, et al., Anesthesiology, 77:324-335 (1992); Kohane, et al., Anesthesiology, 89:1199-1208 (1998)). The literature suggests that a small molecule's hydrophobicity has a U-shaped effect on its ability to penetrate biological barriers (Bernards and H. F. Hill, Anesthesiology 77(4):750-6 (1992)): drugs with an intermediate degree of hydrophobicity penetrate more effectively than those that are very hydrophobic or very hydrophilic. There are some data to suggest that this relationship holds true for local anesthetics penetrating to or into peripheral nerve (Barnet, et al., Pain 110:432-438 (2004)).
A number of methods have been used in the attempt to increase the duration of action of local anesthetics. A method currently used in medical practice is the co-administration of vasoconstrictors such as epinephrine (adrenaline), phenylephrine, or norepinephrine, which increase the residence time of the drug at the site of administration, due to the induction of vasoconstriction with subsequent reduction of systemic uptake of the local anesthetic or biodegradable polymer matrices (U.S. Pat. No. 5,618,563) and glucocorticoids (U.S. Pat. No. 5,700,485).
Chemical permeation enhancers (CPEs) have been used to increase the permeability of the lipid-protein barriers of the skin, and thereby increase drug flux, for over thirty years (Bauerova, K. et al., Eur J Drug Metab Pharmacokinet 200126(1-2): 85-94; Asbill, C. S., et al. Crit Rev Ther Drug Carrier Syst 17(6): 621-658 (2000); Kanikkannan, N., Curr Med Chem 7(6):593-608 (2000); Karande, et al., J Control Release 110:307-313 (2006)). Surfactants, a heterogeneous group of amphiphilic organic molecules with hydrophilic heads and hydrophobic tails, are a well-known class of CPEs. Several sub-classes of surfactants have been studied in the context of transdermal permeation, and are believed to reversibly modify lipids by adsorption at interfaces and removal of water-soluble agents that act as plasticizers (Middleton, J. D. J Soc Cosmet Chem 20:399-403 (1969); Ribaud, C., et al. Pharm Res 11:1414-1418 (1994)). Cationic surfactants are known to produce greater increases in permeant flux than anionic surfactants, which, in turn, increase permeability more than nonionic surfactants (Stoughton, R. B. In: E. M. Farber (Ed.), Psoriasis, Grune and Stratton, Orlando, Fla., 1982. p. 346-398; Kushla, et al., J Pharm Sci 82:1118-1122 (1993); Shen, et al., J Pharm Sci 65:1780-1783 (1976)). A broad range of non-surfactant chemical enhancers has also been investigated (e.g., alcohols, sulfoxides, polyols, fatty acids, esters, terpenes, and cyclodextrins), (Middleton, J Soc Cosmet Chem 20:399-403 (1969); Ribaud, C., et al. Pharm Res 11:1414-1418 (1994); Stoughton, R. B., In: E. M. Farber (Ed.), Psoriasis, Grune and Stratton, Orlando, Fla., 1982. p. 346-398; Kushla, G. P., J Pharm Sci, 82:1118-1122 (1993); Shen, W. W., et al., J Pharm Sci 65:1780-1783 (1976); R. B. Walker and E. W. Smith. Adv Drug Delivery Rev, 18:295-301 (1996)).
U.S. Pat. No. 6,455,066 to Fischer, et al., for example, describes the use of intradermal penetrating agents triglyceride, an aloe composition, and a mixture thereof for topical local anesthetic administration. U.S. Pat. No. 6,673,363 to Luo, et al. describes the use of organic or inorganic permeation enhancers for the delivery of anesthetic agents. U.S. Pat. No. 6,326,020 to Kohane, et al., describes the combination of naturally occurring site 1 sodium channel blockers such as tetrodotoxin with other agents such as another local anesthetic, a vasoconstrictor, glucocorticoid, adrenergic drugs, or amphiphilic or lipophilic solvent to improve the duration of block.
There is still a need for a composition that can provide prolonged nerve block while avoiding systemic toxicity.
It is an object of the present invention to provide a composition for use as an anesthetic with increased potency and efficacy.
It is still another method of the invention to provide a method for local anesthesia that avoids systemic toxicity due to the local anesthetic and provides prolonged nerve block.